Evidence of tenofovir resistance in chronic hepatitis B virus (HBV) infection: An observational case series of South African adults

Abstract

Introduction Tenofovir disoproxil fumarate (TDF) is widely recommended for treatment of chronic hepatitis B virus (HBV) infection because it is safe, affordable and has a high genetic barrier to resistance. TDF resistance associated mutations (RAMs) have been reported, but data are limited, particularly for Africa. We set out to identify potential RAMs in individuals with detectable HBV viraemia on TDF treatment. Methods We recruited adults with chronic HBV infection from Cape Town, South Africa, identifying individuals with a TDF resistance phenotype, defined as persistent HBV vireamia despite >12 months of TDF treatment. We sequenced HBV DNA using MiSeq Illumina with whole genome target enrichment, and sought potential TDF RAMs, based on a pre-defined list of polymorphisms. Results Among 66 individuals with chronic HBV (genotypes A and D), three met our clinical definition for TDF resistance, of whom two were coinfected with HIV. In one participant, the consensus HBV sequence contained nine polymorphisms that have been described in association with TDF resistance. Significant treatment non-adherence in this individual was unlikely, as HIV RNA was suppressed. TDF RAMs were also present in HBV sequences from the other two participants, but other factors including treatment non-adherence may also have had a role in failure of HBV DNA suppression in these cases. Discussion Our findings add to the evidence that RAMs in HBV reverse transcriptase may underpin a TDF resistant phenotype. This is the first time these RAMs have been reported from Africa in association with clinical evidence of TDF resistance.

Endemic HBV among hospital in-patients in Bangladesh, including evidence of occult infection

“…Emerging reports suggest that RT polymorphisms can be associated with reduced TDF susceptibility [ 41 ]. Among these, L217R was present as consensus in sample 118 (55 % of reads) and V191I was identified as a minority variant (28 % reads) ( Table 1 ).…”

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“…TAF also demonstrates broad cross-genotype activity against wild-type HBV clinical isolates and is effective against multidrug-resistant HBV isolates in vitro ( 23 ). Despite high genetic barriers to TFV, emerging evidence has reported that extensive amino acid substitutions were associated with reduced TFV sensitivity, described in both treatment- naïve and -experienced individuals with CHB ( 6 , 8 , 10 ) in Asia, Africa, and Europe. Moreover, in a clinical setting, 0.8–24% patients exhibited a partial response to TDF, while some developed viral breakthrough despite good adherence to TDF ( 25 , 26 ).…”

“…However, several problems are increasingly emerging with long-term antiviral therapy. First, drug resistance is gradually increasing, including resistance to ETV and TDF (5)(6)(7)(8)(9)(10). Second, a diminished estimated glomerular filtration rate, hypophosphatemia, hyperphosphaturia, and Fanconi syndrome have been reported in patients using TDF (11)(12)(13).…”

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“…Recent reports from Korea demonstrated TDF‐resistant HBV mutants in a treatment‐naïve patient 73 as well as two patients who had previously developed virological breakthrough during mono‐ and combination therapy with other NAs 74 . Furthermore, a recent case series of 66 African patients with CHB suggested possible TDF resistance in three patients including two patients coinfected with HIV 75 . The emergence of TDF‐resistant HBV mutants following short‐term TDF exposure in consecutive pregnancies is unclear but predicted to be extremely rare 24 …”

“…74 Furthermore, a recent case series of 66 African patients with CHB suggested possible TDF resistance in three patients including two patients coinfected with HIV. 75 The emergence of TDF-resistant HBV mutants following short-term TDF exposure in consecutive pregnancies is unclear but predicted to be extremely rare. 24 All studies that assessed antiviral potency of TDF in pregnant patients with CHB demonstrated that TDF is associated with a reduction in HBV-DNA levels at delivery versus baseline, 17 ,18,20,21,29,32-39,76 even in pregnant CHB patients resistant to LAM or LdT.…”